Isoxazole, a five-membered heterocyclic ring with an oxygen atom adjacent to a nitrogen atom, is often used in medicinal chemistry since it can be used for a wide variety of protein targets and provides advantageous physical and chemical properties when integrated into a potential drug compound. Specifically, 3,5-dimethylisoxazole containing compounds have garnered interest since they inhibit bromodomain, and the extra-terminal domain family of bromodomains, which are target for cancer treatments. Efficacy studies have been performed on these ligands, but the field's knowledge of the metabolism and subsesequent toxicity risk of these ligands is lacking. Here, we report that in many cases, bromodomain inhibitor ligands with 3,5-dimethylisoxazole that are under development have a relatively high likelihood of forming highly reactive quinone-species in reactions. We also present strategic modifications that lower the likelihood of quinone formation, without modifying key interactions between the ligand and the bromodomain binding pocket. Our study uses three different computational models of metabolism to infer if a quinone is likely to form, what the quinone metabolite structure is, and how likely it is to be reactive towards protein across a set of 3,5-dimethylisoxazole bromodomain inhibitor ligands obtained from the literature. Therefore, our modelling efforts provide directly testable hypotheses that can guide experimentalists to better understand the metabolism and toxicity risks of 3,5-dimethylisoxaxole bromodomain inhibitor ligands. We validate that each of these models are highly accurate by evaluating them with isoxazole-specific test sets we derived from the accelrys metabolite database.

Assessing the liability of isoxazole containing compounds to form reactive metabolites

2019 Fall National Meeting

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